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`
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`AMN1037
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`The Property of
`Stem, Kessiar, Goidstein & Fox, P.L.L.c.
`
`60
`
`2006
`
`EDITION
`
`
`
`
`
`DESK
`REFERENCE
`
`Senior Vice President, PDR Sales and Marketing: Dikran N. Barsamian
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`Copyright © 2006 and published by Thomson PDFi at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
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`may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical,
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`ii
`FER
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`ISBN: 1—56363-526/
`
`2
`
`

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`Solage®
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`(mequinol 2%, tretinoin
`Betaseron®
`0.01% topical solution, 30 mL)
`(Interferon beta-1b)
`"The name BEACH appears on the reverse side of these tahtets.
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`AGE” .1
`Balamine DM Oral Drops
`For Oral Use Only
`1;3 months
`3-6 months
`6-9 months
`9-18 months
`Balamine DM Syrup
`18 months—6 years
`'"
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`6 years and over
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`PHYSICIANS' DESK REFERENC
`—,_*\E®
`Themechanism ofaction'of.mequinol15 unknown Alt
`mequinol'15a substrate for the enzyme tyrosinaSe W011},
`as a competitive inhibitor of the formation of Inelall
`31211
`cursors, the clinical significance of theserfindmga Dre
`known. Theyrrnechanism of action of tretinoin as a Id311111
`menting agent also1s unknown.
`“ W911,
`PHARMACOKINETICS
`
`- The percutaneous absorption of tretinoin and the5'3
`exposure to tretinoin and mequinol were 3.55988:ElIiiQ
`healthy subjects (11:8)following two weeks of tweesedr1111
`topical treatment ofsolagé solution.Approximately..08:3in
`o'f Solagé Solution was applied to a 400 cm2 area} 1111,
`back, corresponding to a dose of 37.3 uglcm2 for 111803311
`' and 0.23 11'g/cm2 for tretinoin. Th’e percutaueous 111130 “"101
`of tretinoin was approximately 4.4%, and systemic'.10
`.01
`trations did notincrease over endogenous levels The
`C111,; for meguinol was 992 ng/mL (range 4.22 to236111:1111
`m‘L)‘and the Tm“.was 2hou " (range 1 to 211mm)
`“El
`INDICATIONS AND-_USAGE
`(To understand fully the indication for this product15111;,
`read the entire INDICATIONSAND uSAGE “@1013;se
`labeling).
`teh
`Solagé (mequinol 2%, tretinoin 0.01%) Topical 301114111
`indicated for the treatment of solar lentigines
`vision as an adjunct to a comprehensive skin care andp;r
`S'olagé Solution should only be used under medical Sue
`
`avoidance program where the patient shouldprim1113!in “’1
`ther avoid the sun or use protective clothing.
`y'e‘
`Neither the safety nor effectiveness of Solagé $011,1110nno“
`the prevention 0r treatmentofgmelasma or postinfiammor
`tory hyperpigmentation has been established.
`a
`The efficacy of using Solagé Solutiondaily for greater th
`24 weeks has not been established.
`
`an
`
`The local cutaneous safety of using Solagé SolutiOn111 min.
`Caucasians has not been adequately established (5136‘ Clin.
`ical Studies section).
`a I
`CONTRAINDICATIONS
`
`-
`
`The combination of mequinol and tretinoin may cause fetal
`harm when administered to a pregnant woman Due to the
`known efi'ects oftheseactive ingredients,Solagé Topical
`Solution should not be used in women of childbearing
`potential.
`In a dermal teratology studyIn New Zealand White rabbits
`there were no statistically significant differences among
`treatment groups in fetal malformation data; however
`marked hydrocephaly with visible doming of the head was
`observedin one mid-dose litter-(:12 and 0106-;mg/kgor 132
`. and 066 mg/m2 of mequinol and tretinoin, respectively) and
`two fetusesIn one high dose litter (40 and 0.2 mg/kg or31.10
`and 2.2.1'11g/m2 of mequinol and tretinoin, respectively) of
`Solage’ Solution, and two high-dose. tretinoin (0.2 mg/kg,
`2.2‘ng/m ) treated litters These malformations were con
`sideredto be treatment related and due to the known effects
`of tretinoin. This was further supportedby coincident ap
`pearance ofother malfbrmations associated with tretinoin,
`such as cleft palateand appendicularkkeletal defects N0
`elfects attnbuted to treatment were observedin rabbitsin
`that study treated topically with mequinol alone ((1059
`40 mg/kg, 440mg/mz) Ano-observed-effect level (NOEL))fO'
`teratogen1c1ty 1tinrabbits Was established at 4 311d
`- 0.02 mg/kg' (44 and 0.22 ni"g/m2 mequinol and tretinoin; 19'
`spectively) for Solagé Solution which1s approximatély the
`maximum possible human:dailydose'z-Ebased on clinical3P
`plication to 5% oftotal body surface area. Plasma tretinoin
`concentrations were not raised above endogenous levels.
`even at teratog'enic doses. Plasma mequinol concentration5
`in rabbits at the NOEL at one hour after application We-9
`D
`124 -ng/mL or approximately twelve times- the mean Pia
`plasma concentrations of thatsubstance seen in. hufl'l“
`subjectsin a clinical pharmacokinetic stud. In a repeatted
`istudy'1n pregnant rabbits administeredthesame-21195919"
`els as the study described above,,additional precaufiflnei,15
`measures were taken to prevent ingestion, although theytla
`no evidence to confirm that ingestion occurred i114?he ini
`study. Precautionary measures additionally limi'ted trail:
`dermal absorptiomto a Sixhour exposure pdiiod 01111111101”
`imately one-fourth— of the human clinical daily 001mm“1
`exposure time. This study did not show any sigmfi‘3‘7'n“t W
`atogenic efi°_e'cts at doses up to approximately.13 “west
`human dose on» a mg/m2 basis. However, a concur?e
`tinoin dose group (02 mg/kg/day)did include W
`01057
`with limb malformations,
`In a published study111 albino rats (J. Am. Coll; Toxicliflfl
`4(5):31—63 1985). topical application of 5% arm'equinflan
`cream vehicle during- gestationwas e1nb1-yot0X1c an,s‘noted
`bryolethal. Embryonic loss priorto implantationWas ”as
`in that study where animals were treated throughout on111”
`tation. Coincidentally, mean preimplantation embgino]
`loss was increased'in thefirst rabbit studyIn all meqeme'
`treated groups, relative to control,and'In the high.605:1 the
`quinol/tretinbin and tretinoin only treated groupsstation
`second study. In those studies, dosing began at. gas eased
`day 6, when implantation15 purported to occur more1,111”
`preimplantation loss was also noted” at the high CO swag
`tion doseIn a study of early embryonic e'ifects inrats?39 £011
`decreased bodyweight1n male pups; these findmgsa
`sisterit with.the published study.
`331,11}:
`Solagé Solution was not teratogenic1nSpra'gue. gm
`rats when given in topical doses of 80 ‘and 0.4 111ka
`’
`quinol and tretinoin, respectively (480 and 24 mg/m1111331,",
`times the maximum human daily dose). The maximed (15")
`- man dose1s defined as the amount‘ ofsolution 31311118
`to 5% of the total bodysurface area.
`(I
`.
`
`
`
`
`
`* In mild cases ,or in particularlysensitive‘patients, less frequent or reduced doses may be “adequate.
`.
`1
`..
`.
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`anticonvulsants to controlCNS excitation..and convulsions.
`Balamine DM—Cont.
`h) Physostigmine may,.reverse antichohnergicrsymptoms,,
`-
`i) Ammonium chloride may acidify the urine to increase
`111111313’ excretlori 0f pseudoephedrme J') Furthercare 15'
`coughand take caution that modification of cough does"not
`symptomatic and SUPPQI'tlYe
`‘
`incre'a'se the risk of clinical or physiologic complications
`DOSAGE AND ADMINISTRATION
`Dextromethorphan should be used with caution in sedated
`[See table above]
`\.
`or debilitated patients andIn patients confined to supine
`positions.
`R 1
`HOW SUPPLIED
`Use "with caution in patients with hypertension, hear't
`Balamine DM Oral Drops, grape flavored 111 30 11-11, bottles
`disease, asthma, hyperthyroidism, increased intrao'culat
`withcalibrated droppers, NDC 63162-509-30
`pressure, diabetes mellitus and prostatichypertrophy.
`‘
`' Balamine DM Syrup, grape flavored, 111 16-fl oz. (1_1,1111)
`Information for Patients: Avoid alcohol and other CNS de-'
`bottles, NDC 63162-50816
`pressants while taking these products. Patients sensitive to
`Dispense1n USP tight, lightresistant container.Avoidvex-
`antihistaminesmay experience moderate tosevere d1'QWS'1‘
`111351111930 excessive heat
`1.
`1,1
`.
`-;
`ness. Patientssensitive to sympathom‘i'metic amines may
`
`Rx ONLY
`nite mild CNS Stimulation. While taking these produets,
`Revised 12/01
`exercise care indriving or operatingappliances, machinery,
`‘1‘:
`BALLAY
`etc
`Drug Interactions Antihistamines may enhance the 9f' Manufactured for-2
`fects of tricyclic antidepressants, barbiturates, alcohol, and
`other CNSdepressants. MAO inhibitors prolong and inten-
`sify the'anticholinergic‘ effects of antihistamines.‘
`Sympathomimetic amines may reduce the antihypertensive -—"‘—'—-—-——
`effects of reserpi‘ne, veratrurn alkaloids, methy'ldopa a'nd
`«'1
`mecamylamine. Efl‘ects of sympathomimetics are increased
`with MAO inhibitors and beta--adrenergic blockers The
`cough-suppressant action ofdextromethorphan and narcotic
`antitussives are additive. Dextromethorpha'nIs contraindi-
`cated with monoamine oxidase inhibitors (MAOI). See 0611-.
`traindications section
`.Anirn'al reproduction studies have
`PregnancyCategory C.
`not been conducted with Balamine DM. It1s also‘not known
`whether these products can cause fetal harm when admin-
`istered to apregnant woman or affect reproduction capacity.
`Give to pregnant women only if clearlyneeded.
`.
`Nursing} Mothers:
`It is not known whether the drugsin
`Balamine DM are excreted'inhuman milk. Becausemany -
`drugsare excretedin human milk and because ofthe_poten-.
`'tial forserious adverse reactions1n nursingginfants, a deci-
`sion should be made whether to discontinue nursingiordiVs-
`continue the product, taking into accountthe importance of
`thedrugtothe mother.‘
`.
`-
`ADVERSE REACTIONS “L
`Antihistamines: Sedation, dizziness, diplopia, vorhitingt
`diarrhea, 'dry mouth, headache, neryousness, nausea,
`:
`anorexia, heartburn,weakness, p01
`a and dysuri'a and,
`rarely, exc1tab111ty1nch11drenUrinary retentionmayOccur
`inpatients with prostatic hypertrophy.‘
`Sympathomimetic Amines. Convulsions, CNS stimulation,
`cardiac arrhythmias, respiratory difficulty. increased:heart
`rate or blood. pressure, hallucinations tremors, nervous- .
`ness, insomnia, weakness, pallor and 'dysuria.
`Dextromethorphan: Drowsiness, dizziness, . 'and GI
`disturbance
`.
`‘ i
`'
`OVERDOSAGE
`No. informationis available as to specific results of anover— 7
`dose of these products. The signs, symptoms and treatment
`described belowaare those of H1 antihistamine, ephedrine
`anddextromethorphan overdose.
`Symptoms. Should antihistamine effects predominate,
`central actionconstitutes the greatest danger. In the small
`child, predominant symptoms are excitation, hallucination
`ataxia, incoordination-,utremors, flushedface and fever.
`_
`Convulsions, fixed and dilated pupils, coma and death may
`occur in severe cases In the adult, fever and flushing are
`uncommon; excitement leading to convulsions and postictal
`depressionis often preceded by dr0wsines's andcoma. Res-
`pirationisusually not seriouslydepressed, bloodpressureis
`usually stable. -
`‘ " '
`'
`>'
`"
`CLINICAL PHARMACOLQGY
`Should sympathomimetic symptoms predominate, central
`Solar lentigines are localized, pigmented, macular lesions of
`effects include restlessness, dizziness, trémor, hyperactive
`the skin on the areas of the body which have been chroni-
`reflexes, talkativeness, irritability and insomnia Cardio-
`Cally exposed to sunlight.
`vascular and. renal effects include difficultyin micturi'tion,
`Biopsy specimens of solar lentigines were collectedin a clin-
`headache, fliishing, palpitatioi'i, cardiac arrhythmias,1 hy‘
`ical study with Solagé Solution at "baseline, at the end of a
`pertefisioh with subsequent hypotension and circulatory
`24 week treatment period and at the eIid of a subsequent 24
`collapse. Gastrointestinal effects 'include dry mouth, metal-
`week, no treatment, follow-up period. Theend of treatment
`lic taste, anorexia, nausea, vomiting, diarrhea, and abdom-
`specimens showed a decrease in melanin pigmentation in
`inal cramps.
`-’
`bothmelanocytes and keratinocytes, and an increasedl-ym
`Dextromethorphan may/cause respiratorydepression with a
`phocytic infiltration, which may have been the result ofIr-
`large overdose.
`ritation or an immunologic reaction. The end of follow--up
`Treatment:
`a) Evacuate stomach as condition warrants.
`period specimens showed repigmentation of the melano-
`Activated charcoal may be useful. b) Maintain a non-
`cytes and keratinocytes to a state similar to the baseline
`stimulating environment. c) Monitor cardiovascular status.
`specimens. These results indicate that thereisno assurance
`d) Do not give stimulants. e) Reduce fever with coolspong-
`that any improvement obtained would persist upon discon—
`ing. 1') Treat respiratory depression with naloxone if dextro-
`tinuation of drug therapy
`methorphan toxicityis suspected. g) Use sedatives or
`Information willbe superseded by supplementsand subsequent editions
`
`Ba‘llay»Pharmaceuiicals, Inc,
`Wimber'le'y, 13;. '78676
`
`,3
`
`.
`
`_
`
`2
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`?-
`
`,
`
`'
`
`,
`
`:
`
`,
`(1,
`
`‘
`
`'
`
`Direct Inquiries to:
`Phonezv866—440-5508 _
`"
`1
`
`'7.
`
`-' B‘
`
`-
`
`'
`
`1
`t
`SOLAGF®.
`[5‘7laj—"1 1 1
`lmequlnol 2'%' tret""°'“ °-'01%)
`‘Toplcal $0lufl°n .
`For Dermatologlc.use only Not for- ophthalmic, ora'lzor
`Intravaglnal‘ use
`Rx only
`“‘3‘
`1
`*
`—
`.
`DESCRIPTION
`d t _
`l 217
`e
`ta'
`Sol
`é® T .
`1 S 1 ton
`89
`re
`0 an
`con ms 111 quino
`opica
`0 u 1
`tinoin 0.01%, by weight, in. a solution base of ethyl alcohol
`(77.18% v/v), polyethylene glycol400,-butylated hydroxytolu-
`asc bic acid .c't
`id
`rli 1‘
`lm't t
`ed t be (1'
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`ne,
`or
`1 ri_c ac
`asc'o y pa
`1 a e,
`e a
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`sodiumand purifiedwater
`"‘7'
`glequmdIS 4hfid;°?anisoie’ tliehmo'no ethyl ether-’Ofby’
`gag-muff? or 1
`.C I??? -me 10X
`
`C zmflca tormuai'f7 8 12’ a 1110 cc
`an t e S' ructpra ormua.
`
`H CO+OH3
`3
`-
`-
`.1
`'
`
`The chemical name for tretinoin, a retinoid,',15 (allE)-37-
`dimethyl-9-(2,6,6-:trimethyl-1-cyclohexen-l-yl)-2,4,6,8--non-
`atetraenoicacid, alsoreferred to as all-trans-retinoic acid It
`-' has the chemical formula, 020112502: a molecular weight of
`300.44, and the structural formula.
`a
`‘-
`
`
`
`"
`
`4
`
`.14“; =“
`
`
`
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`
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`

`
`
`
`
`BARRIER/741
`
`
`Adverse Events.Oécut¥ing-Tin=>1% of the Population —All Studies
`
`,
`Lady System,
`Solagé Solution1 I
`
`(mequinol‘2%,
`‘
`-
`nJ
`Tretinoin,
`Mequinol,;
`
`__.‘,-tretirloin 0.91%)
`.
`,
`,gx-
`0.01[%'
`2%
`'” This“.
`.l
`%,
`%'
`.
`N
`at
`N
`Skiniand ”f
`
`Appendages
`.,
`_
`. m -
`VS I
`'
`
`549
`44.6
`261
`55.3
`. 13
`5.1 '
`8'
`‘
`Erythenia
`4.6.
`Biirning/Stinging/
`" .
`27o
`.219
`173
`i 36.7
`—26‘
`10:2
`- 20 .
`- 11.4
`Tingling
`'
`
`Desduamation‘
`'155-
`I
`‘
`93
`19.7
`'
`-7
`2.8'
`2
`1.1E
`
`.
`.
`,
`..
`.
`i
`(
`
`Pruriti‘is w
`135"
`‘66
`14.0
`12.
`4.7
`3
`17
`I—
`
`Vehicle
`
`%
`
`
`Irritation Skin
`90
`25
`5.31
`1
`”0.4,
`1
`‘ 0.6
`Hat;
`_i
`76
`16
`3 4
`2
`0.8
`2
`1 1
`
`I
`;
`Hypopigmentation
`1,
`.
`
`Hypopi'gmentation
`50 3"
`'
`1.7
`2,
`08
`P70
`0.0 .
`
`Skin or;
`38
`‘
`l
`3gs
`3'
`1.2» —I
`1‘
`0.6
`Rash
`31 '
`4 4"
`o
`oo
`1
`0.6-h-
`I
`2.5
`21
`i
`
`Crusting
`30
`2.4
`18
`3-58 .4
`-0 :
`0.0
`1
`0.6‘
`-
`I
`Rash vesicular
`18
`2:1
`see
`1.7
`0
`0.0
`o
`0.0
`Bullae
`r
`
`
`Dermatitis
`.
`
`
`
`
`i
`
`
`
`
`. Face
`' ForéafnislBack of Hands
`
`
`
`
`Solagé Solution L ' Nehicle
`Solagé Solutidn ’I
`r
`' -
`1‘
`V
`Moderate Improvement
`57%
`.15,%'l
`.-
`.
`‘~
`'54%
`
`
`r x
`or greaterl‘
`- r'
`w,
`I)
`337/221;
`28%“ ”A
`Slight Improvement
`36%:
`26%
`IR?
`No Change2 --
`.;
`49%
`{20%
`' 53%-
`n
`1
`llncludes the following grades: Moderate Improvement, Marked Improvement, Almost Clear, CompIetely ClearjModLei‘ate
`Improvement or greater was considered clinicallymfeaningfill.
`glncludes the following grades:.Nn*Qhange,.Worse (less than 1%‘of, patients fireatedgwith sgsiagé Squtidn were rated as
`
`4
`>1
`worse).
`
`
`. Se o
` f any drug, a smallrnurnbér ofbirth
`p“?3
`.
`.
`.
`dated terfiporally’w1ththe administra-
`th Mde fiS'iat’isO- 1d beexpefited by chance alone. Thirty
`MW r9190drug W"u associated congenital'malforfnations
`‘an of ”’9. Wmufiuring two "decades of clinical use of an-
`“051:5 of ”reported f topical tretinoin. Although 'no definite
`“a“, bee“ u anon 0. ity«and no casuallassociation' has been
`bier {oflftewwgémce case‘s, '6 at the reports describe the
`”1 Mm o :1 fiom‘thes ory holoprosencephaly (defects assoi
`PaablIShe
`f Ct 633539 midline development of the ‘for’e‘l
`'t
`incOIPP nee of these spontaneous reports in
`is- I!
`WI
`"-si nlfica
`at known.“No>adequate‘10r well-
`,
`.
`- ,the
`femagen’conducted with Sblagé; Solution
`115k toé have
`”meiotion ‘is contraindicated in individuals
`. Topical 5.0 nsitivjty reactions to any ‘of its ingredi-
`e
`u
`.
`.
`x.
`i
`. tor); (if Sgiscontinued if hypersensitivity to. an
`
`1
`is nvtéd'
`.
`..
`.
`;.
` acne-"s , ,i i;- v r,
`
`.
`.-n is adermal iratant'and the results of con-
`Solagé Soilltlfln of thQiSkjni for greater- than 52wee‘ks in
`.~ ue
`imtatl‘?» .use are gnotiknqwn- Tretniom has been
`"nmniét longiie;
`severe im‘t‘ation on eczematous skin and
`re:ported to 22332117 withl uthS‘P, caution in patients with
`ld be. ‘1
`.
`~:'
`.
`,
`35111;;wnditiofl-activeneslI5 9f_Solage,Solutionem individuals
`a .
`Sfi‘ggggfidyfi orj'heaVflY pigmented,,sk1n».haye*-not been
`Lglmblisgeittion shgfilg notzhe administeredifthe patient is
`soles]e _°
`',._ known toybe photosens1tizers,(e.g., film;
`“'50
`mg “tines” i-luoroquinolones, phenothiazinesj
`
`”Kai
`,
`ridgsaafifégg beciiiisfi ofiithexpossibi-lity. of raugmen
`.
`),
`an o
`.
`,.
`7
`.
`,
`.
`ph'owwmcétiieightenéd burning susceptibility; exposure to
`Bece“? (3.1101,,de'gnnlampsftoyht ated areas should be
`5“".hght 1minimized durinthhe useIQf-‘Solagé Solution. 13a-
`“.VOldei’d 9;; be advised to use protective clothingand comply
`
`"in“ ”a reh’en‘ve sunearoidance-prggramcwhen 1ising
`
`mm 3, “Silfim bate»;
`not available to: establish how or
`3:53; Solagé Solutiongis degraded (either by sunlight or
`by normalyinterior lighting) following application to the
`skin. Patients with Sunburn Should. lie adVised .not to use
`Solagé sointion’nntilfullyrecovered.»,Pat1ents who. may
`have considerable sneexroseredeeno their Oppepatloeand
`those patients with inherent sensitivityto sunlight $110914
`exercise particular caution when using Solagé Solution and
`ensure that the precautions outlined in the Patient Medica;
`lion Guide are observed.
`,
`,.
`,
`:7
`Solagé Solution should bekep'tput of the eyes, mouth, para-
`nosal creaseskand mucous membranes. Solagé, Solution
`may cause skin irritation, erythema,,burning, stinging-fir
`tingling, peeling,.and pruritis. If the degreeJ-of such local ir-
`ritation warrants; patients, should be directed to-use less
`medication,»decrease the-frequency of application; discon--
`tinue use temporarily, or discontinue use altogether. The
`efficacy at reduced frequencies of application has not been
`established.
`x
`'
`‘-
`:31
`'1"
`I
`,
`Solagé Solution should,,be-us,ed with caution by’ patients
`with a history, prgfamily, history, of vitiligo._ One patientjin
`the trials, Whose brother had vitiligo, experienced hypopig;
`mentation in areas that had not, been treated with study
`fixation. Some'of these areas, contmued to worsen for at
`weeksoéletmonth ppst treatment with, §qlagé Solution. Six
`creased Eetfiheseveqty of ther'hypopigmentation had de:
`the pane “tililmilderate to mild and 106 days post treatment,
`Apniieatii:
`ad resolution of somebut ,notlall lesmns.
`mended ernof larger amounts of, medication than recom;
`marked rehnélsit JeacIto, more rapid or better results, and
`of the skin may Bgfif‘ymg, discomfort, or hypopigmentation
`PRECAU'rIoNs
`'
`" 4'
`
`
`
`brain
`
`,
`
`I
`i
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mal-ilse‘onl‘y;
`olagé Solutiol'ltshou
`prehensive ski
`ld only be used as an adjunct to‘a com-
`CATTONS n carei‘afid sun avoidance program. (See IN-
`.I'ug sens‘t‘ ~
`.USAGE Section).
`L '5 I
`‘1
`{I
`‘2
`“me reactionléylty, ‘Chemic'al imitation, or a systemicvad-
`discofltinued WBVelops; use of Solage Solution should'be
`be
`e lmtat' Bather. 615611511165, such as wind or cold, may
`mafia“ f mg to patients using Solagé Solution:
`°fpat1ents"
`7;- :1. 33
`benefits .311quHe detailed instruction"to obtain maximal
`prod
`"
`.
`use tin"
`0 Understand all the precautions necessary to
`Drum teractlilcfiigut},l ETBatestvsafe‘ty
`i‘
`”"
`'
`.
`.
`.
`it
`'
`ant t0D_lcal products With alstrong skin drying ef-
`“entl .piees 0r li
`13h concentrations of alcohol, astrin-
`e solutiome’ medicated soaps or shampoos, perma-
`eparaiis’ electrolysm, hair depilatories or waxes,
`.
`e used Wions that might dry ‘or irritate the skin
`agfiSollltion blth Caution in patients being treated with
`Sula “f1
`Ola
`, WEI—Use they niay increase irritation when
`“1509.6 Solutio 9e SOliltron.
`.
`' g (in? ShOUId not be administered ifthe patient is
`. acycli
`own to be photosensitizers (e.g., thia:
`[Thu mules) b Iles,
`fluoroquinolones,
`'phenothiazines,
`ec511156 of the possibility of augmented
`Mt
`'-
`.
`Catsgiga31:5 NIUta
`u
`a
`.
`genesis, lm‘pairmen‘t of'Fertility
`
`cal‘drlogenicity study in CD-1 mice i’ndii
`1.2:? to aidswaoé
`Solution applie'dutopically at daily doses
`e
`.
`“1013) $823.4
`“lg/kg (240 and 1:2 mg/mz) of mequinol and
`
`ctlvely, representing approximately 5‘ times
`
`
`
`
`
`
`
`'
`
`the maic‘imum‘possib e systemic human exposingwas not
`;a'rc_iiiogenic, Jin a: photocarcinogenicityf study tilizing
`Crlz'Skh—Hhr/hr BR) hairless albino mice, mediéi‘
`time to
`onszetiofitnmor's, d'ecréased.’Also, the, number qf tfirnprs in;
`creashdiifi all dose groiips‘administe'i‘ed' 1.4343 on 14 111 of
`§iildgé Solution/cm? of skin (24 ‘é‘i‘id ’0.1'2,
`'72 and 0.36,”o:r
`240 and 1:2 ing/m2 (of mequinol and tretinoin, respectively?
`0.6, 1.9,'or‘6.5 times the .daily human dose onVa mg/m? basis)
`following "chronic topical desing with intercurrer'it exposure
`to ultraviolet radiation for up, 130.40 weeks, Siinilar animal
`studies have shown an increased tumorigenic risk‘ with the
`useI nfretinoids when ‘followed by iiltriviolet radiation. Al-
`though they‘significan’ce of these studies to human use is not
`cleaf, patientsf'u'sing this product should be advised to avoid
`or minimize exposure to either sunlight or artificial ultravi-
`olet irradiation sources”.
`"
`'
`‘
`‘5 "I
`Mequinol Wasnon-mutag'enic in the Ames/Salmonella assay
`
`using strains TABB, TAIOO, TA1535, VaridTA‘1537, allfloflf
`which are in'j‘iisit'ive' to mutage'nic efl‘ects' of'structur‘allyL
`
`related'quindiie fSoliaQ'é Solution was non—genotoxic in an
`in vivo dermal micronucleus assay in rats'fb'ut exposure of
`bone marrow to drug was not demonstrated.
`,
`‘
`A dermal reproduction study? With. rSbiagé Solution in
`SpraguehDawley rats at a daily dose of 80 and 0.4%mg/kg
`(480 and 2:.4'mg/11'12) of,mequinol and ,tre'tiiioin, respectively,
`approximately 11 times the cérrespor’iding maximum possi-
`ble human exposure; assuming 100% bioavailability follow—
`ing .topical application to 5% ‘bf the total_ body surface
`area, showed‘ no impairment of fertility.
`'IJ
`,
`Pregnancy: Terétogenic effects: Pregn'anéy Category’X.’ ’
`Although- the magnitudefo the potential for teratogenicity
`may ‘notkbe well-defined; Solag'é‘Sohition is labeled as an
`“X’f because the potential risk of the use of this drug'to treat
`this particular indication (solar le‘ntigines) in a pregnant
`woman clearly outweighs any! possible benefitisee 'CON-
`TRAINDIC’ATIONS sectiim)? '
`‘
`’
`Nursing Mothers:
`It is‘ not known to what extent mequinol
`and/or tretinoin is excreted inhuman milk. Because many
`drugs are excreted-in human milk, caution should be exer-
`cised when Solagé Solution is administered to’anursing
`woman.
`.
`_
`Pediatric Use; The safety and efl‘ectiveness of this product
`have not been established in pediatric patients. SpiragéESo-
`lotion should not be used ori‘childreni.’
`Gefiiétric V_Use':
`;_,O_f thetotalrnumber rof patients‘in clinical
`studies onSOIaéé Solu ,ion, approximately43% were '65‘ and
`older, while approximately 8% were 75.‘and OVer. No overall
`diH‘erences in éfi'ehtiTveiiéss' Or safety were observed between
`these patients and younger patients.
`‘
`ADVERSE REACTIONS ..
`‘
`In clinical trials, adverse reactions were primarily‘mild to
`moderate in intensity, occurringin 66% and 30% ofpatients,
`
`
`
`
`
`
`
`
`
`
`
`respectively. The majority of these events "Were limited'to -
`the skin and 64% had an onset of a skin related adverse
`reaction early in treatment (by week 8); The mostfrequent
`adverse‘reactions in patients treated virith Solag'é'Solution
`wbre erythema (49%tof patients), burning, stinging, or'3tin-
`gling (26%), desquaniation 614%), pruritus (12%),: and skin
`irritation (5%).
`«
`~
`..
`i
`’
`Some patients experienced temponar-y hypopigmentation of
`treated, lesions (5%) or of the,_skin surrounding treated le—
`sions L(7%). Ninety—four of 106 patients (89%),had resolution
`of hypopigmgntation upon discontmuation of treatment to
`the lesion,,and/or réiinstruction on proper application to the
`lesion only. Another 8% (9/106) of patients with .hypopig-
`mentation events had resolution within 120; days after'the
`end of treatmenti'TI‘hree of the 106 patients (2.8%) had per:
`sistenpe of hypopigmentation beyond 120. days. 'Approxi—
`mately 6% of patients discontinued study participation with
`Solagé Solution due to1advers